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Ankyrin repeat and kinase domain containing 1 (ANKK1) is a member of the receptor-interacting protein serine/threonine kinase family, known to be involved in cell proliferation, differentiation and activation of transcription factors. Genetic variation within the  ANKK1  locus is suggested to play a role in vulnerability to addictions. However,  ANKK1  mechanism of action is still poorly understood. It has been suggested that  ANKK1  may affect the development and/or functioning of dopaminergic pathways. To test this hypothesis, we generated a CRISPR-Cas9 loss of function  ankk1  zebrafish line causing a 27 bp insertion that disrupts the  ankk1  sequence introducing an early stop codon. We found that  ankk1  transcript levels were significantly lower in  ankk1  mutant ( ankk1 27 ins   ) fish compared to their wild type ( ankk1  +/+ ) siblings. In  ankk1  +/+  adult zebrafish brain, ankk1 protein was detected in isocortex, hippocampus, basolateral amygdala, mesencephalon, and cerebellum, resembling the mammalian distribution pattern. In contrast, ankk1 protein was reduced in the brain of  ankk1 27 ins/ 27 ins    fish. Quantitative polymerase chain reaction analysis revealed an increase in expression of  drd2b  mRNA in  ankk1 27 ins    at both larval and adult stages. In  ankk1  +/+  adult zebrafish brain, drd2 protein was detected in cerebral cortex, cerebellum, hippocampus, and caudate homolog regions, resembling the pattern in humans. In contrast, drd2 expression was reduced in cortical regions of  ankk1 27 ins/ 27 ins    being predominantly found in the hindbrain. No differences in the number of cell bodies or axonal projections detected by anti-tyrosine hydroxylase immunostaining on 3 days post fertilization (dpf) larvae were found. Behavioral analysis revealed altered sensitivity to effects of both amisulpride and apomorphine on locomotion and startle habituation, consistent with a broad loss of both pre and post synaptic receptors.  Ankk1 27 ins    mutants showed reduced sensitivity to the effect of the selective dopamine receptor antagonist amisulpride on locomotor responses to acoustic startle and were differentially sensitive to the effects of the non-selective dopamine agonist apomorphine on both locomotion and habituation. Taken together, our findings strengthen the hypothesis of a functional relationship between  ANKK1  and  DRD2 , supporting a role for  ANKK1  in the maintenance and/or functioning of dopaminergic pathways. Further work is needed to disentangle  ANKK1 ’s role at different developmental stages.

Ankk1 Loss of Function Disrupts Dopaminergic Pathways in Zebrafish